DESCRIPTION: Diabetes is a rapidly growing global health problem. While diabetic neuropathy (DN) and peripheral arterial disease (PAD) are among the most common complications, there are no effective therapies. Diabetic neuropathy (DN) affects 60% of diabetic patients, and is characterized by damage to the neural vasculature as well as to neuronal cells. Advanced PAD in diabetes frequently affects small vessels such that conventional interventional and surgical treatments are ineffective, and frequently leads to limb loss. Studies have shown that bone marrow-derived mesenchymal stem cells (MSCs) are effective in treating cardiovascular diseases and DN. However, MSCs derived from diabetic subjects were reported to be less functional, and epigenetic chromatin changes were suggested to underlie this dysfunction. Emerging evidence has shown that small molecular epigenetic modifiers can change key chromatin remodeling enzymes and alter cellular function. Another main problem for cell therapy is low cell retention in vivo and a bioengineering approach has emerged to overcome this pitfall. Accordingly, we propose to restore the function of diabetic MSCs using small molecular epigenetic modifiers and apply these reprogrammed diabetic MSCs in combination with biomaterials for the treatment of diabetic neural and vascular complications. We will then determine their therapeutic effects on well-established animal models of diabetic PAD and DN. We anticipate that this study will yield novel insight into the chromatin alterations of MSCs in diabetes and suggest the potential therapeutic utility of reprogrammed MSCs for treating various diabetes-related neural and vascular complications in an autologous manner. Given the safety of MSCs, this approach can be easily translated into a pilot clinical trial once the efficacy is established by this study.